Effect of Food on the Bioavailability of 30 mg Estetrol (E4) Tablet in Healthy Postmenopausal Female Volunteers

An Open-label, Single-center, Randomized, Two Period, Two Sequence Crossover Study to Characterize the Effect of Food on the Bioavailability of 30 mg Estetrol (E4) Tablet in Healthy Postmenopausal Female Volunteers

Assessment of the effect of a high fat meal on the quantity in blood of a female sex hormone called estetrol (E4).

The study also aims at determining how subject tolerate the study drug and how safe it is for them.

Study Overview

• Status: Completed
• Conditions: Food-effect
• Intervention / Treatment: Drug: 30 mg estetrol (E4)

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria
    • MC Comac Medical Ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Overtly healthy postmenopausal females as determined by medical history, physical examination including breast examination, gynecological examination, cervical smear (Pap smear) if subject has cervix, vital signs, and laboratory tests performed within 28 days before first study drug intake.
• Between the ages of 40 and 65 years inclusive at the time of signing the informed consent (IC).
• Between the Body Mass Index (BMI) of 18 and 30 kg/m2 inclusive and body weight ≥ 45 kg.
• For non-hysterectomized women: intact uterus with bi-layer endometrial thickness ≤ 5 mm on transvaginal ultrasound (TVUS).
• Non-smokers.
• Negative test results for selected drugs of abuse and cotinine.
• Venous access sufficient to allow blood sampling as per the protocol.
• Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.
• Subject has provided signed and dated written IC before participation in the study.

Exclusion Criteria:

• For non-hysterectomized women: uterine disease or medical condition including:

  • Bi-layer endometrial thickness >5mm as determined by TVUS;
  • Presence of fibroid(s) that obscure(s) evaluation of endometrium by TVUS;
  • History or presence of uterine cancer;
  • Presence of any significant uterine, ovarian or other adnexa related abnormality as determined by TVUS;
  • Presence of an endometrial polyp.
• Undiagnosed vaginal bleeding in the last 12 months.
• Any history of malignancy.
• History of venous or arterial thromboembolic disease
• Abnormal blood pressure.

• Use of :

  • Any prescription drugs within 28 days prior to the first study dose administration.
  • Any over-the-counter (OTC) medication or dietary supplements (vitamins included) within 14 days prior to the first study dose administration.
• Users of progestin implants or oestrogen alone injectable drug therapy are not allowed to participate unless treatment was stopped more than 3 months prior to screening.
• Users of oestrogen pellet or progestin injectable drug therapy are not allowed to participate unless treatment was stopped more than 6 months prior to screening.
• Subjects who are not in euthyroid condition.
• History of hypersensitivity or existing contraindication to E4 or intolerance to any component of the formulations or test meal.
• Presence or history of gallbladder disease, unless cholecystectomy has been performed.
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study.
• History or presence of immunodeficiency diseases including a positive human immunodeficiency virus (HIV) test result, positive hepatitis B surface antigen (HBsAg) or hepatitis C test result.
• History of illicit drug or alcohol abuse within 12 months prior to first study dose or evidence of such abuse as indicated by laboratory values within 28 days prior to first study dose.
• Consumption of foods or beverages containing the following products during the specified timeframes prior to study drug administration in Period 1: caffeine or xanthine - 48 hours; alcohol - 48 hours; grapefruit/seville orange/citrus fruit and/or star fruit - 7 days. Others Fruit juices: 72 hours prior to study drug administration.

• Donation or loss of

  • ≥ 450 mL blood within 1 month prior to initial study drug administration.
  • ≥ 250 mL blood within 2 weeks prior to initial study drug administration.
• Sponsor, Contract Research Organization (CRO) or Investigator's site personnel or their relatives directly affiliated with this study.
• History or presence of clinically relevant disease of any major system organ class (SOC) (e.g. cardiovascular, pulmonary, renal, hepatic, gastrointestinal, reproductive, endocrinological, neurological, psychiatric or orthopedic disease) as judged by the Investigator.
• Previous completion or withdrawal from this study.
• Participation in another investigational drug clinical study within 1 month (30 days) or have received an investigational drug within the last 3 months (90 days) prior to study entry.
• Is judged by the Investigator to be unsuitable for any reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 30 mg estetrol (E4) without food (fasted); Treatment A (reference): One 30 mg E4 tablet administered orally following an overnight fast of at least 10 hours.	Drug: 30 mg estetrol (E4); All subjects received both Treatment A and Treatment B either at the first treatment period (Period 1) or at the second treatment period (Period 2). Approximately half of the subjects was randomized to receive either Treatment A followed by Treatment B (sequence AB), or Treatment B followed by Treatment A (sequence BA).; Other Names: 30 mg E4 tablet
Experimental: 30 mg estetrol (E4) with food (fed); Treatment B (test): One 30 mg E4 tablet administered orally 30 min after the start of an FDA prescribed high-fat breakfast preceded by at least a 10 hours overnight fast.	Drug: 30 mg estetrol (E4); All subjects received both Treatment A and Treatment B either at the first treatment period (Period 1) or at the second treatment period (Period 2). Approximately half of the subjects was randomized to receive either Treatment A followed by Treatment B (sequence AB), or Treatment B followed by Treatment A (sequence BA).; Other Names: 30 mg E4 tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum concentration (Cmax) of Estetrol in plasma	PK sampling	Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
Area under the curve (AUC) from time zero to the last determinable concentration of Estetrol	PK sampling	Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
AUC0-inf of Estetrol	PK sampling	Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of Cmax (Tmax)	PK sampling	Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
Terminal phase rate constant (ke)	PK sampling	Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
Terminal half-life (t1/2)	PK sampling	Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
Number of subjects with adverse events as measure of safety and tolerability		From Day 28 prior screening to end of study (Day 4 of Period 2)

Collaborators and Investigators

• Sponsor: Donesta Bioscience
• Investigators: Principal Investigator: Dobrin Svinarov, MD, MC Comac Medical Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2019
• Primary Completion (Actual): April 6, 2019
• Study Completion (Actual): April 6, 2019

Study Registration Dates

• First Submitted: January 7, 2019
• First Submitted That Met QC Criteria: January 7, 2019
• First Posted (Actual): January 9, 2019

Study Record Updates

• Last Update Posted (Actual): May 7, 2019
• Last Update Submitted That Met QC Criteria: May 3, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Estetrol; Menopausal hormone therapy
• Other Study ID Numbers: MIT-Do001-C101; 2018-003761-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No